title: The prognostic significance of BMP-6 signaling in prostate cancer.
abstract: The importance of bone-morphogenetic proteins in prostate cancer is well recognized. Bone-morphogenetic protein-6 overexpression has been shown to increase the aggressiveness and invasiveness of prostate cancer cells. Recent studies on noggin and sclerostin, potent inhibitors of bone-morphogenetic protein signaling, have found that noggin also modifies the ability of prostate cancer cells to metastasize to bone. Taken together, these results suggest that bone-morphogenetic protein-6 signaling is important in prostate cancer progression. Our study investigated the expression of bone-morphogenetic protein-6, noggin and sclerostin in human prostate specimens (n=136) by immunohistochemical staining. We found that bone-morphogenetic protein-6 was increased (P<0.001), whereas sclerostin was decreased (P=0.004) in prostate cancer compared with nodular hyperplasia. In addition, significantly higher level of bone-morphogenetic protein-6 expression was observed in high-grade prostate cancer with Gleason score >or=7 (P=0.027). Bone-morphogenetic protein-6, noggin and sclerostin alone could not predict the development of distant metastasis in our patient cohort. However, high level of bone-morphogenetic protein-6 and low level of noggin, or high level of bone-morphogenetic protein-6 and low level of both noggin and sclerostin expression in primary prostate cancer significantly predicted development of distant metastasis. The predictive value was still valid when only high-grade prostate cancers were included or when patients with secondary lesion other than bone were excluded. Taken together, these results suggest that a high level of bone-morphogenetic protein-6 signaling, resulting from increased expression of bone-morphogenetic protein-6 and decreased expression of its inhibitors, might promote the development of prostate cancer metastases. Our results also imply the potential use of bone-morphogenetic protein-6, noggin and sclerostin expression together as a prognostic predictor for metastatic progression of prostate cancer.
authors.affiliation: Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Hiu-Fung
authors.initials: HF
authors.lastname: Yuen
authors.forename: Yuen-Piu
authors.initials: YP
authors.lastname: Chan
authors.forename: Wai-Lok
authors.initials: WL
authors.lastname: Cheung
authors.forename: Yong-Chuan
authors.initials: YC
authors.lastname: Wong
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wang
authors.forename: Kwok-Wah
authors.initials: KW
authors.lastname: Chan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D055418:Bone Morphogenetic Protein 6 / Q000096:biosynthesis*; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis*; D002352:Carrier Proteins / Q000096:biosynthesis*; D018450:Disease Progression; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D000099176:Noggin Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D005819:Genetic Markers; D000099176:Noggin Protein; C525816:BMP6 protein, human; C422903:SOST protein, human